ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Variant summary: RAD51D c.904-3C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. Experimental evidence supports these predictions indicating the variant has no effect on splicing (Casadei_2019). The variant allele was found at a frequency of 0.00024 in 253596 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.904-3C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, Lynch Syndrome and pancreatic ductal adenocarcinoma (Osher_2012, Tung_2015, Yurgelun_2015, Chaffee_2018), however it was also observed in controls (Loveday_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

The RAD51D c.904-3C>T variant was identified in 3 of 9008 proband chromosomes (frequency: 0.0003) from individuals or families with colorectal, breast and ovarian cancer and was present in 1 of 2120 control chromosomes (frequency: 0.004) from healthy individuals (Yurgelun 2015, Osher 2012, Tung 2015, Loveday 2011). The variant was identified in dbSNP (rs45478491) as “with uncertain significance allele” and ClinVar (classified as likely benign by Ambry Genetics, Color and 2 other submitters and uncertain significance by Invitae, Counsyl and 1 other submitter and benign by GeneDx). The variant was identified in control databases in 63 of 277,232 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,038 chromosomes (freq: 0.0002), Other in 2 of 6468 chromosomes (freq: 0.0003), Latino in 7 of 34,420 chromosomes (freq: 0.0002), European in 50 of 126,710 chromosomes (freq: 0.0004), but was not observed in the Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The c.904-3C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. The variant occurs at a non-conserved nucleotide and 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.